WO2001056606A1 - Remedes pour troubles ophtalmiques - Google Patents

Remedes pour troubles ophtalmiques Download PDF

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Publication number
WO2001056606A1
WO2001056606A1 PCT/JP2001/000617 JP0100617W WO0156606A1 WO 2001056606 A1 WO2001056606 A1 WO 2001056606A1 JP 0100617 W JP0100617 W JP 0100617W WO 0156606 A1 WO0156606 A1 WO 0156606A1
Authority
WO
WIPO (PCT)
Prior art keywords
retinal
disease
interleukin
inhibitory activity
optic nerve
Prior art date
Application number
PCT/JP2001/000617
Other languages
English (en)
Japanese (ja)
Inventor
Hideaki Hara
Shinji Yoneda
Nobuaki Miyawaki
Hidenobu Tanihara
Original Assignee
Santen Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Santen Pharmaceutical Co., Ltd. filed Critical Santen Pharmaceutical Co., Ltd.
Priority to EP01948940A priority Critical patent/EP1252895A4/fr
Priority to CA002398900A priority patent/CA2398900A1/fr
Priority to AU2001228863A priority patent/AU2001228863A1/en
Publication of WO2001056606A1 publication Critical patent/WO2001056606A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • C07K16/245—IL-1
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1793—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1841—Transforming growth factor [TGF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2006—IL-1
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/38—Albumins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • the present invention relates to a protective agent for optic nerve cells and a remedy for eye diseases comprising a compound having an interleukin-11 inhibitory activity as an active ingredient.
  • the retina has the function of receiving light from the outside, and plays an important role in visual function. Structurally, it is a 0.1-0.5 mm thick tissue consisting of 10 layers, including the retinal pigment epidermis, inner plexiform layer, ganglion cell layer, nerve fiber layer, etc.
  • inner plexiform layer there are neurons that form synapses in pairs with ganglion cell processes called amacrine cells. Since this responds well to the start and end of light irradiation, it is thought to work as a light intensity detector.
  • the ganglion cell layer contains nerve cells whose cell bodies are located inside the retina, and is deeply involved in motor vision, peripheral vision, color vision, morphology, and the like.
  • retinal vessels which are branches of the central retinal artery and vein, run, and play a role in supplying oxygen and nutrients to the optic nerve.
  • retinal blood circulation When retinal blood vessels are obstructed or narrowed by factors such as spasm, thrombosis, and atherosclerosis, retinal blood circulation is impaired, and oxygen and nutrient supply to the retina and optic nerve are shut off.
  • Disorders of retinal blood circulation are particularly important among retinal diseases. Representative examples of symptoms associated with impaired retinal blood circulation include retinal vascular occlusion in which retinal veins and retinal arteries are occluded or narrowed, diabetic retinopathy that contributes to retinal detachment, and visual impairment If you have ischemic optic neuropathy.
  • the impaired retinal blood circulation causes a shortage of oxygen and nutrient supply, and retinal ganglion cells die. In other retinal diseases such as macular degeneration, retinitis pigmentosa, and label disease, this ganglion cell death is considered to be deeply involved in the onset.0
  • apoptosis which is a form of programmed cell death, is involved in various pathological conditions in eye diseases. For example, retinal damage due to ischemia-reperfusion (J. Ocul.
  • IL-1 interleukin-11
  • IL-Ira interleukin-1 receptor antagonism
  • IL-1ra administered intraventricularly in a rat cerebral ischemia model (Brain Res. Bull., 29, 243-246, 1992) or IL-11 neutralizing antibody (Stroke, 26, 676-681, 1995) have been reported to suppress ischemic encephalopathy.
  • WO97 / 41844 shows that an angiogenesis inhibitor combining IL-Ira and tumor necrosis factor (TNF) antagonist can suppress the appearance of pathological neovascular vessels.
  • WO966Z093323 describes that IL-11ra has an inflammation-suppressing action and an immunosuppressive action.
  • Japanese Patent Application Laid-Open No. 5-32072 discloses that a protoporphyrin IX zinc (II) complex having an IL-1 inhibitory activity or an IL-11 neutralizing antibody reduces ischemic cerebral edema. Is described.
  • Retinal vaso-occlusive disease diabetic retinopathy, ischemic optic neuropathy
  • ocular diseases such as retinal diseases such as macular degeneration, retinitis pigmentosa, and label disease, and glaucoma
  • eye tissues especially retinal ganglia.
  • optic nerve cells such as cells.
  • the present inventors have conducted intensive studies using various animal models and found that optic nerve cells can be protected by suppressing the action of interleukin-11.
  • interleukin-11 damages optic nerve cells, and that by suppressing their function, optic nerve cells can be protected.
  • it acts on and uses the interleukin-11 receptor and acts as an endogenous interloukin-11 receptor antagonist that acts antagonistically to interleukin-11.
  • the protection of optic nerve cells is achieved by administering an interleukin-11 neutralizing antibody that directly acts on gonist protein (IL-1ra) or interleukin-11 and inhibits its action. I found what I could do.
  • eye diseases such as retinal disease and glaucoma.
  • eye diseases such as retinal diseases and glaucoma include retinal vascular occlusion, diabetic retinopathy, ischemic optic neuropathy, macular degeneration, retinitis pigmentosa, and label disease.
  • the present invention relates to a protective agent for optic nerve cells such as retinal ganglion cells, comprising a compound having an interleukin-1 (IL-1) inhibitory activity as an active ingredient, and more specifically, retinal diseases, glaucoma, etc. It is intended to provide a therapeutic agent for eye diseases.
  • compounds having an interleukin-1 inhibitory activity include compounds having an antagonistic effect on IL-11 (for example, endogenous IL-11 receptor antagonist protein such as anakinra, soluble IL, etc.).
  • Endogenous IL-11 receptor analogs such as 1 receptor and IL-11 receptor
  • IL 1 Endogenous IL-11 analogs, such as mutant and IL-11-derived peptides
  • SL Compounds that inhibit the activity of IL-1 or IL-1 eg, neutralizing IL-11, transforming growth factor (TGF) - ⁇ , melanocyte stimulating hormone
  • examples include dalcocorticoids such as dexamethasone-prednisolone, and protoporphyrin IX zinc (II) complex
  • compounds that inhibit the production or release of IL-11 eg, Hydro Guayare Click acid and re Pokishigenaze inhibitors such as gallic acid ⁇ - propyl, phosphodiesterase inhibitors such as mouth Li plums, etc.
  • Hydro Guayare Click acid and re Pokishigenaze inhibitors such as gallic acid ⁇ - propyl, phosphodiesterase inhibitors such as mouth Li plums, etc.
  • the compound having the interleukin-11 inhibitory activity according to the present invention.
  • the effect of the substance on the optic nerve cells will be described in detail in the section on pharmacological tests below, but the effect on the ischemia induced by water pressure ischemia. Effects on injury, N-methyl-D-aspartate (NMDA) -induced retinal injury Investigation of the effect on retinal ganglion cells revealed a remarkable inhibitory effect on cell number reduction in the retinal ganglion cell layer and an effect on thinning of the inner plexiform layer. In addition, when examining the effect on intraocular pressure, an excellent intraocular pressure lowering effect was confirmed.
  • NMDA N-methyl-D-aspartate
  • the route of administration of the compound having interleukin-11 inhibitory activity according to the present invention may be parenteral or oral.
  • Parenteral dosage forms include eye drops, injections, nasal drops, etc.
  • Oral dosage forms include tablets, capsules, fine granules, granules, powders, etc. These can be formulated using commonly used techniques.
  • isotonic agents such as sodium chloride and concentrated glycerin
  • buffering agents such as sodium phosphate and sodium acetate
  • Surfactants such as tanmonate, polyoxyl stearate 40, and polyoxyethylene hydrogenated castor oil
  • preservatives such as benzalkonium chloride, paraben, etc. can be used as needed, and the formulation can be made.
  • the pH should be within the acceptable range for ophthalmic preparations, but in the range of 4 to 8. Is preferred.
  • the dose can be appropriately selected according to the symptoms, age, dosage form, etc., but for eye drops, 0.01 to L0% (wZv) should be instilled once to several times a day.
  • 0.01 to L0% (wZv) should be instilled once to several times a day.
  • 0.01 to 1 mg per day may be administered once or in several divided doses.
  • 10 ⁇ g to 1 g per day can be administered once or in several divided doses.
  • IL-1 interleukin-11
  • NMDA N-methyl-D-aspartate
  • Rats were anesthetized with 3% halothane and maintained at 1% halothane (halothane was vaporized with 0.5 LZ of oxygen and 1.5 L / min of laughter).
  • halothane was vaporized with 0.5 LZ of oxygen and 1.5 L / min of laughter.
  • the right eye is dilated in the right eye with the A-to-mouth pin ophthalmic solution, and a 30 G syringe needle with a saline solution ophthalmic container suspended from the ceiling and connected via a tube is inserted into the anterior chamber.
  • a water pressure of 130 nimHg was applied to induce ischemia.
  • the injection needle was removed, and retinal blood flow was reperfused.
  • the group that received the ischemia by administering the solvent and the group that received the ischemia by administering IL-11ra dissolved in the solvent were called the “solvent-administered group” and the “IL-11ra-administered group”, respectively.
  • Three slices were randomly selected from the eight slices prepared at intervals so that the optic disc could enter each eye, and a photograph of the retina between 1 and 1.5 mm on either side of the optic disc for the selected slice Photographs were taken and the number of cells in the ganglion cell layer (GCL) and the thickness of the inner plexiform layer (IPL) in the retina were measured. These results were compared with the corresponding measured values for the “normal (untreated) group” that had not been treated at all. Table 1 shows the experimental results. The values in the table indicate average values.
  • Rats under 1% halothane anesthesia were subjected to an ischemic load for 45 minutes in the same manner as in (1) above.
  • 10 mM phosphate buffered saline solution (solvent) and IL-1 neutralizing antibody (50 ng Z eyes) dissolved in the solvent were administered intravitreally 5 minutes before the ischemic load, and administered 7 days after administration. Later, the eyes were enucleated. Thereafter, the same operation as in the above (1) was performed, and the number of cells in the ganglion cell layer (GCL) in the retina and the And the thickness of the inner plexiform layer (IPL) were measured.
  • GCL ganglion cell layer
  • IPL thickness of the inner plexiform layer
  • IL-1ra was dissolved in physiological saline (solvent) to prepare a test drug of 10 gZm 1.
  • a test drug 10 gZm 1.
  • 0.4% oxyprocaine hydrochloride ophthalmic solution drop by drop into both eyes of male Japanese White Egret and local anesthesia
  • intraocular pressure was measured using an applanation tonometer.
  • the test drug (201) was administered into the anterior chamber of one eye using a 30 G needle syringe.
  • 0.4% oxyprocaine hydrochloride ophthalmic solution was instilled into the administered eye drop by drop, and local anesthesia was performed. Then, intraocular pressure was measured.
  • IL-1ra endogenous interleukin-1 receptor antagonist protein
  • Tables 1-3 Administer endogenous interleukin-1 receptor antagonist protein (IL-1ra) or interleukin-1 neutralizing antibody into the vitreous, as shown in Tables 1-3. This markedly suppresses the decrease in the number of cells in the ganglion cell layer and the thinning of the inner plexiform layer. Moreover, as is clear from Table 4, IL-1ra has an excellent intraocular pressure lowering effect. According to the results of such pharmacological tests, a therapeutic agent for ophthalmic diseases containing a compound having interleukin-1 inhibitory activity as an active ingredient is effective in producing optic nerve cells such as retinal ganglion cells caused by interleukin-1.
  • optic nerve cells such as retinal ganglion cells caused by interleukin-1.
  • Protective agent and therapeutic agent for retinal diseases such as retinal vascular obstruction, diabetic retinopathy, ischemic optic neuropathy, macular degeneration, retinitis pigmentosa, label disease, etc. and eye diseases such as glaucoma Useful. Industrial applicability.
  • the present invention provides a protective agent for optic nerve cells such as retinal ganglion cells and a therapeutic agent for ophthalmic diseases such as glaucoma and retinal diseases, comprising a compound having an interleukin-11 inhibitory activity as an active ingredient.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Ophthalmology & Optometry (AREA)
  • Biochemistry (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Cardiology (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cell Biology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à des remèdes pour troubles ophtalmiques tels que le glaucome et les affections rétiniennes. Les composés présentant une activité d'inhibition de l'interleukine-1 (les protéines antagonistes des récepteurs de l'interleukine-1 endogènes, les anticorps neutralisant l'interleukine-1) présentent des effets remarquables s'agissant d'inhiber la réduction du nombre de cellules dans la couche des cellules ganglionnaires de la rétine, d'empêcher l'amincissement de la couche endorétinienne et d'abaisser la tension oculaire.
PCT/JP2001/000617 2000-01-31 2001-01-30 Remedes pour troubles ophtalmiques WO2001056606A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP01948940A EP1252895A4 (fr) 2000-01-31 2001-01-30 Remedes pour troubles ophtalmiques
CA002398900A CA2398900A1 (fr) 2000-01-31 2001-01-30 Agents therapeutiques pour troubles ophtalmiques
AU2001228863A AU2001228863A1 (en) 2000-01-31 2001-01-30 Remedies for ophthalmic diseases

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2000021446 2000-01-31
JP2000-21446 2000-01-31
JP2000268829 2000-09-05
JP2000-268829 2000-09-05

Publications (1)

Publication Number Publication Date
WO2001056606A1 true WO2001056606A1 (fr) 2001-08-09

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ID=26584457

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2001/000617 WO2001056606A1 (fr) 2000-01-31 2001-01-30 Remedes pour troubles ophtalmiques

Country Status (4)

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EP (1) EP1252895A4 (fr)
AU (1) AU2001228863A1 (fr)
CA (1) CA2398900A1 (fr)
WO (1) WO2001056606A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120014970A1 (en) * 2009-01-09 2012-01-19 Reza Dana Therapeutic Compositions for Treatment of Corneal Disorders
US8252945B2 (en) 2005-04-13 2012-08-28 Ube Industries, Ltd. Protective agent for retinal neuronal cell comprising indazole derivative as active ingredient
US9138438B2 (en) 2005-03-31 2015-09-22 Asahi Glass Company, Limited Method for protecting a retinal neuronal cell
US10117906B2 (en) 2009-01-09 2018-11-06 The Schepens Eye Research Institute, Inc. Methods for reducing corneal nerves damage, corneal lymphangiogenesis or immunity to corneal antigens in dry-eye associated ocular surface diseases by IL-1Ra

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Publication number Priority date Publication date Assignee Title
EP0234855A2 (fr) * 1986-02-19 1987-09-02 Eye Research Institute Of Retina Foundation Préparation pour la stimulation de la sécrétion de larmes comprenant des hormones stimulantes de mélanocyte
WO1988007380A1 (fr) * 1987-03-25 1988-10-06 Pharmacia Ab Composition pour le traitement topique du glaucome ou de l'hypertension oculaire
WO1991003245A1 (fr) * 1989-08-28 1991-03-21 Alcon Laboratories, Inc. Composition ophtalmique
JPH05320072A (ja) * 1992-05-20 1993-12-03 Taiho Yakuhin Kogyo Kk 虚血性脳疾患治療薬
WO1994001124A1 (fr) * 1992-07-08 1994-01-20 Celtrix Pharmaceuticals, Inc. PROCEDE POUR TRAITER DES AFFECTIONS OPHTALMIQUES A L'AIDE DU FACTEUR TRANSFORMANT DE CROISSANCE-$g(b)
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WO1991003245A1 (fr) * 1989-08-28 1991-03-21 Alcon Laboratories, Inc. Composition ophtalmique
JPH05320072A (ja) * 1992-05-20 1993-12-03 Taiho Yakuhin Kogyo Kk 虚血性脳疾患治療薬
WO1994001124A1 (fr) * 1992-07-08 1994-01-20 Celtrix Pharmaceuticals, Inc. PROCEDE POUR TRAITER DES AFFECTIONS OPHTALMIQUES A L'AIDE DU FACTEUR TRANSFORMANT DE CROISSANCE-$g(b)
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KEANE-MYERS, ANDREA M. ET AL.: "Prevention of allergic eye disease by treatment with IL-1 receptor antagonist", INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, vol. 40, no. 12, 1999, pages 3041 - 3046, XP002945055 *
KIDO N. ET AL.: "Neuroprotective effects of interleukin-1-beta and interluekin-1 receptor antagonist in eyes with NMDA-induced", VISUAL SCIENCE, vol. 41, no. 4, 15 March 2000 (2000-03-15), pages S15, XP002945053 *
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9138438B2 (en) 2005-03-31 2015-09-22 Asahi Glass Company, Limited Method for protecting a retinal neuronal cell
US8252945B2 (en) 2005-04-13 2012-08-28 Ube Industries, Ltd. Protective agent for retinal neuronal cell comprising indazole derivative as active ingredient
US20120014970A1 (en) * 2009-01-09 2012-01-19 Reza Dana Therapeutic Compositions for Treatment of Corneal Disorders
US10117906B2 (en) 2009-01-09 2018-11-06 The Schepens Eye Research Institute, Inc. Methods for reducing corneal nerves damage, corneal lymphangiogenesis or immunity to corneal antigens in dry-eye associated ocular surface diseases by IL-1Ra

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CA2398900A1 (fr) 2001-08-09
AU2001228863A1 (en) 2001-08-14
EP1252895A4 (fr) 2003-04-16
EP1252895A1 (fr) 2002-10-30

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